This invention relates to a novel series of 5-(arylsulfonyl)-,5-(arylsulfinyl), and 5-(arylsulfanyl)-thiazolidine-2,4-diones of formula (I) to their use in cancer therapy, to pharmaceutical compositions containing them, and to a process for their preparation. The compounds are inhibitors of Ras FPTase, and may be used as an alternative to, or in conjunction with, traditional cancer therapy for treating ras- oncogene-dependent tumors, such as cancers of the pancreas, colon, bladder, and thyroid. Compounds in the invention may also be useful for controlling metastasis, suppressing angiogenesis, inducing apoptosis, and in treating Ras-associated proliferative diseases other than cancer, such as restenosis, neuro-fibromatosis, endometriosis, and psoriasis. These compounds may also inhibit prenylation of proteins other than Ras, and thus be effective in the treatment of diseases associated with other prenyl modifications of proteins.
Mammalian H-, K-, and N-Ras proteins, encoded by H-, K-, and N-ras proto-oncogenes, respectively, are 21 kD GTP-binding proteins which possess intrinsic GTPase activity and play a fundamental role in cell proliferation and differentiation (G. L. Bolton, J. S. Sebolt-Leopold, and J. C. Hodges, Annu. Rep. Med. Chem., 1994, 29, 165; R. J. A. Grand in xe2x80x9cNew Molecular Targets in Cancer Chemotherapyxe2x80x9d J. D. Kerr, and P. Workman, Eds., CRC Press, Boca Raton, Fla., 1994, p. 97). Specific mutations in the ras gene impair GTPase activity of Ras, leading to uninterrupted growth signals and to the transformation of normal cells into malignant phenotypes. Mutant ras oncogenes are found in approximately 25% of all human cancers, including 90% of pancreatic, 50% of colon, and 50% of thyroid tumors (J. L. Bos, Cancer Res., 1989, 49, 4682). It has been shown that normal cells transfected with mutant ras gene become cancerous and that unfarnesylated, cytosolic mutant Ras protein does not anchor in cell membranes and cannot induce this transformation (J. F. Hancock, H. Paterson, and C. J. Marshall, Cell, 1990, 63,133). Posttranslational modification and plasma membrane association of mutant Ras is essential for this transforming activity. The first and required step in the processing of Ras is farnesylation at the cysteine residue of its carboxyl terminal motif, CAAX (C=Cys-186, A=aliphatic amino acid, X=usually methionine, serine or glutamine). Since its identification, the enzyme farnesyl-protein transferase (FPTase) that catalyzes this first processing step has emerged as a promising target for therapeutic intervention (H.-W. Park, S. R. Boduluri, J. F. Moomaw, P. J. Casey, and L. S. Beese, Science, 1997, 275, 1800; P. J. Casey, P. A. Solski, C. J. Der, and J. E. Buss, Proc. Natl. Acad. Sci. U.S.A., 1989, 86, 8323; S. Ayral-Kaloustian and J. S. Skotnicki, Annu. Rep. Med. Chem., 1996, 31, 165, and references therein). Major milestones have been achieved with small molecules, such as mimics of the tetrapeptide CAAX and analogs of farnesyl pyrophosphate, that show efficacy without toxicity in vitro as well as in mouse models bearing ras-dependent tumors or human xenografts with H-, N-, or K-ras mutations (S. Ayral-Kaloustian and J. S. Skotnicki, Annu. Rep. Med. Chem., 1996, 31, 165, and references therein; T. M. Williams, Exp. Opin. Ther. Patents, 1998, 8, 553, and references therein). Several low-molecular weight compounds that inhibit FPTase have entered Phase I trials in humans (SCH-66336, Pharmaprojects, 1998, No. 5128; R-115777, Pharmaprojects, 1998, No. 5532).
5-[3-aryl-prop-2-ynyl]-5-(arylsulfonyl)thiazolidine-2,4-diones and 5-[3-aryl-prop-2-ynyl]-5-(arylsulfanyl)thiazolidine-2,4-diones which possess antihyperglycemic activity, are reported in U.S. Pat. Nos. 5,574,051 and 5,605,918.
Accordingly, there is still a need for drugs for treating and preventing cancer. In particular, there is a need for drugs which inhibit or treat the growth of tumors expressing an activated Ras oncogene and which include cancers of the pancreas, colon, bladder and thyroid.
The present invention disclosed compounds represented by Formula (I): 
wherein:
Ar is 1-naphthyl, 2-naphthyl, 8-quinolinyl, 2-thienyl, 5-chloro-2-thienyl, 5-(2-pyridyl)-2-thienyl, 2-pyridinyl, substituted 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 2-quinolinyl, 2-pyrimidinyl, 2-benzoxazolyl, 2-benzthiazolyl, 2-benzimidazolyl, 2-furanyl, 2-benzo-[b]-furanyl, 2-benzo-[b]-thienyl or a moiety of the formula: 
R1 is hydrogen, fluoro, bromo, chloro, iodo, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms,4-pyridyloxy, azido, nitro, acetamido, trifluoromethoxy, phenoxy, or benzyloxy;
R2 is hydrogen, fluoro, bromo, chloro, iodo, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, trifluoromethoxy, phenoxy, or benzyloxy;
m is 0, 1 or 2;
R6 is hydrogen, alkyl of 1 to 6 carbon atoms, benzyl, substituted benzyl, imidazolylpropyl, or xe2x80x94CO2Y;
Y is 2-methoxyethyl, alkyl is 1 to 6 carbon atoms, benzyl, or substituted benzyl;
W is 
xe2x80x83Exe2x80x94 and Zxe2x80x94xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CONHxe2x80x94, xe2x80x94CONHCH2xe2x80x94, xe2x80x94CONHCH2CH2xe2x80x94, or xe2x80x94CH2xe2x80x94CH2xe2x80x94;
n is an integer of 1 to 9;
Arxe2x80x2 is thienyl, pyridinyl or a moiety of the formula: 
R3, R4, R5, are independently selected from hydrogen, alkoxy of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms, fluoro, bromo, chloro, iodo, nitro, amino, hydroxy, azido, cyano, phenyl, phenoxy, trifluoromethyl, trifluoromethoxy, methanesulphonyl, 1-pyrrolyl, xe2x80x94CO2R7, xe2x80x94CONHR8, xe2x80x94CH2CONHR9, xe2x80x94NHCO2R10, xe2x80x94NHCOR11, and xe2x80x94NHCONHR12;
R7 is selected from H, and alkyl of 1 to 6 carbon atoms,
R8 is selected from H, and alkyl of 1 to 6 carbon atoms;
R9 is selected from H, and alkyl of 1 to 6 carbon atoms;
R10 is selected from alkyl of 1 to 6 carbon atoms, benzyl, nitrobenzyl, and chlorophenyl;
R11 is selected from alkyl of 1 to 6 carbon atoms, benzyl, phenyl, halophenyl, alkyl(1 to 6 carbon atoms)phenyl, alkoxy(1 to 6 carbon atoms)phenyl, and biphenyl;
R12 is benzyl, alkyl of 1 to 6 carbon atoms, alkoxy(1 to 6 carbon atoms)phenyl, halophenyl, and alkyl(1 to 6 carbon atoms)phenyl;
provided that when W is 
xe2x80x83then n is other than 2;
further provided that when n is 1, m is 0 or 2, R6 is H and W is 
xe2x80x83then:
Ar is not phenyl, 2-naphthyl, alkyl substituted phenyl, alkoxy substituted phenyl, halogen substituted phenyl, 2-pyridinyl, substituted 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 2-quinolinyl, 2-pyrimidinyl, 2-benzoxazolyl, 2-benzthiazolyl, 2-benzimidazolyl, 2-furanyl, 2-benzo-[b]-furanyl, 2-thienyl, 2-benzo-[b]-thienyl; and
Arxe2x80x2 is not phenyl, alkyl substituted phenyl, perfluoroalkyl (mono or di)substituted phenyl, halogen substituted phenyl, alkoxy substituted phenyl, perfluoroalkoxy substituted phenyl and alkylthio substituted phenyl;
or pharmaceutically acceptable salts thereof.
Among the preferred groups of compounds of Formula (I) of this invention including pharmaceutically acceptable salts thereof are those in the subgroups below, wherein the other variables of Formula (I) in the subgroups are as defined above wherein:
a.) R6 is hydrogen, n is 3, m is 2, W is 
b.) R6 is hydrogen, n is 3, m is 2, W is 
xe2x80x83Ar is a moiety of the formula: 
c.) R6 is hydrogen, n is 3, m is 2, W is 
xe2x80x83Ar is a moiety of the formula: 
Arxe2x80x2 is a moiety of the formula: 
d.) R6 is hydrogen, n is 3, m is 2, W is 
xe2x80x83Ar is a moiety of the formula: 
Arxe2x80x2 is thienyl or pyridinyl;
e.) R6 is hydrogen, n is 3-6, m is 2, W is 
f.) R6 is hydrogen, n is 3-6, m is 2, W is 
xe2x80x83Ar is a moiety of the formula: 
g.) R6 is hydrogen, n is 3-6, m is 2, W is 
xe2x80x83Ar is a moiety of the formula: 
Arxe2x80x2 is a moiety of the formula: 
h.) R6 is hydrogen, n is 3-6, m is 2, W is 
xe2x80x83Ar is a moiety of the formula: 
Arxe2x80x2 is thienyl or pyridinyl;
i.) R6 is hydrogen, n is 1, m is 2, W is 
j.) R6 is hydrogen, n is 1, m is 2, W is 
xe2x80x83Ar is a moiety of the formula: 
k.) R6 is hydrogen, n is 1, m is 2, W is 
xe2x80x83Ar is a moiety of the formula: 
Arxe2x80x2 is a moiety of the formula: 
l.) R6 is hydrogen, n is 1, m is 2, W is 
xe2x80x83Ar is a moiety of the formula: 
Arxe2x80x2 is thienyl or pyridinyl;
Additionally preferred compounds of this invention include compounds of Formula (I) in which m is 2, Ar is phenyl substituted in the 4-position by iodo, methoxy, trifluoromethoxy, 4-pyridyloxy; Arxe2x80x2 is phenyl substituted in the 2-position by chloro or methyl, and in the 5-position by amino, chloro, a carbamic acid ester, a substituted carboxamide group, or in the 4-position by nitro or a carbamic acid ester; W is an acetylenic group, and n is the integer 3.
Specifically preferred compounds of this invention according to Formula (I) for treating or controlling ras oncogene-dependent tumors and associated proliferative diseases in warm-blooded animals preferably mammals, most preferably humans in need thereof are the following compounds or a pharmaceutically acceptable salt thereof:
5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-methoxyphenylsulfanyl)-thiazolidine-2,4-dione,
5-[6-(4-Chlorophenyl)hex-5-ynyl]-5-(4-methoxyphenylsulfanyl)-thiazolidine-2,4-dione,
5-[11-(4-Chlorophenyl)undec-10-ynyl]-5-(4-methoxyphenylsulfanyl)-thiazolidine-2,4-dione,
5-(4-Methoxyphenylsulfanyl)-5-(5-thiophen-2-yl-pent-4-ynyl)-thiazolidine-2,4-dione,
5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-fluorophenylsulfanyl)-thiazolidine-2,4-dione,
5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-methoxyphenylsulfonyl)-thiazolidine-2,4-dione,
5-[6-(4-Chlorophenyl)hex-5-ynyl]-5-(4-methoxyphenylsulfonyl)-thiazolidine-2,4-dione,
5-[11-(4-Chlorophenyl)undec-10-ynyl]-5-(4-methoxyphenylsulfonyl)-thiazolidine-2,4-dione,
5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-methoxyphenylsulfonyl)-thiazolidine-2,4-dione,
5-[5-(2-Chlorophenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)-thiazolidine-2,4-dione,
5-[5-(3-Chlorophenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)-thiazolidine-2,4-dione,
5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(p-tolylsulfonyl)-thiazolidine-2,4-dione,
5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-iodobenzenesulfonyl)-thiazolidine-2,4-dione,
5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-fluorobenzenesulfonyl)-thiazolidine-2,4-dione,
5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-phenoxybenzenesulfonyl)-thiazolidine-2,4-dione,
5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(naphthalene-2-sulfonyl)-thiazolidine-2,4-dione,
N-(4-{5-[5-(4-Chlorophenyl)pent-4-ynyl]-2,4-dioxothiazolidine-5-sulfonyl}phenyl)acetamide,
5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(quinoline-8-sulfonyl)-thiazolidine-2,4-dione,
5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-nitrobenzenesulfonyl)-thiazolidine-2,4-dione,
5-(4-Benzyloxybenzenesulfonyl)-5-[5-(4-chlorophenyl)pent-4-ynyl]-thiazolidine-2,4-dione,
5-(4-Butoxybenzenesulfonyl)-5-[5-(4-chlorophenyl)-pent-4-ynyl]-thiazolidine-2,4-dione,
5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(naphthalene-1-sulfonyl)-thiazolidine -2,4-dione,
5-[5-(2,5-Dichloro-phenyl)pent-4-ynyl]-5-(4-methoxy-benzenesulfonyl)-thiazolidine-2,4-dione,
5-[5-(2,5-Dichloro-phenyl)pent-4-ynyl]-5-(4-iodobenzenesulfonyl)-thiazolidine-2,4-dione,
5-[5-(2,5-Dichlorophenyl)pent-4-ynyl]-5-[4-(pyridin-4-yloxy)benzenesulfonyl]thiazolidine-2,4-dione,
5-[5-(2,4-Dichlorophenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)-thiazolidine-2,4-dione,
5-(4-Methoxybenzenesulfonyl)-5-[5-(3-nitrophenyl)pent-4-ynyl]-thiazolidine-2,4-dione,
5-[5-(3-Nitrophenyl)pent-4-ynyl]-5-(4-phenoxybenzenesulfonyl)-thiazolidine-2,4-dione,
5-(4-Iodobenzenesulfonyl)-5-[5-(4-nitrophenyl)pent-4-ynyl]-thiazolidine-2,4-dione,
5-(4-Methoxybenzene sulfonyl)-5-[5-(4-nitrophenyl)pent-4-ynyl]-thiazolidine-2,4-dione,
5-(4-Methoxybenzene sulfonyl)-5-[5-(2-methyl-5-nitrophenyl)pent-4-ynyl]-thiazolidine-2,4-dione,
5-(4-Methoxybenzenesulfonyl)-5-[5-(2-methoxy-5-nitrophenyl)pent-4-ynyl]thiazolidine-2,4-dione,
5-[5-(2-Methyl-5-nitrophenyl)pent-4-ynyl]-5-(4-phenoxybenzenesulfonyl)-thiazolidine-2,4-dione,
5-(4-Iodobenzenesulfonyl)-5-[5-(2-methyl-5-nitrophenyl)pent-4-ynyl]-thiazolidine-2,4-dione,
5-[5-(2-Methyl-5-nitrophenyl)-pent-4-ynyl]-5-(naphthalene-1-sulfonyl)-thiazolidine-2,4-dione,
5-[5-(2-Methyl-5-nitrophenyl)pent-4-ynyl]-5-(naphthalene-2-sulfonyl)-thiazolidine-2,4-dione,
5-[5-(2-Methyl-4-nitrophenyl)pent-4-ynyl]-5-[4-(pyridin-4-yloxy)-benzenesulfonyl]-thiazolidine-2,4-dione,
5-[5-(2-Methyl-4-nitrophenyl)pent-4-ynyl]-5-(4-phenoxybenzene-sulfonyl)-thiazolidine-2,4-dione,
5-(4-Methoxybenzenesulfonyl)-5-[5-(2-methyl-4-nitrophenyl)-pent-4-ynyl]-thiazolidine-2,4-dione,
5-(4-Iodobenzenesulfonyl)-5-[5-(2-methyl-4-nitrophenyl)pent-4-ynyl]-thiazolidine-2,4-dione,
5-(4-Methoxybenzenesulfonyl)-5-[5-(2-methoxy-4-nitrophenyl)pent-4-ynyl]-thiazolidine-2,4-dione,
5-[5-(3-Fluoro-5-nitrophenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)-thiazolidine-2,4-dione,
5-[5-(2,5-Dimethylphenyl)pent-4-ynyl]-5-(4-iodobenzenesulfonyl)-thiazolidine-2,4-dione,
5-[5-(2,5-Dimethylphenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)-thiazolidine-2,4-dione,
5-[5-(2,4-Dimethylphenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)-thiazolidine-2,4-dione,
5-[5-(2,4-Dimethylphenyl)pent-4-ynyl]-5-(4-iodobenzenesulfonyl)-thiazolidine-2,4-dione,
5-[5-(5-Chloro-2-methylphenyl)pent-4-ynyl]-5-(4-methoxybenzene-sulfonyl)-thiazolidine-2,4-dione,
5-[5-(5-Chloro-2-methylphenyl)pent-4-ynyl]-5-(4-trifluoromethoxybenzene-sulfonyl)-thiazolidine-2,4-dione,
5-[5-(4-Chloro-2-methylphenyl)pent-4-ynyl]-5-(4-trifluoromethoxy-benzenesulfonyl)-thiazolidine-2,4-dione,
5-[5-(4-Chloro-2-methylphenyl)-pent-4-ynyl]-5-(4-iodobenzenesulfonyl)-thiazolidine-2,4-dione,
5-[5-(4-Chloro-2-methylphenyl)pent-4-ynyl]-5-(4-methoxybenzene-sulfonyl)-thiazolidine-2,4-dione,
5-[5-(4-Bromo-2-methy-phenyl)pent-4-ynyl]-5-(4-methoxybenzene-sulfonyl)-thiazolidine-2,4-dione,
5-[5-(4-Bromo-2-methylphenyl)pent-4-ynyl]-5-(4-iodobenzenesulfonyl)-thiazolidine-2,4-dione,
(4-{5-[5-(4-Methoxybenzensulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}phenyl)carbamic Acid tert-Butyl Ester,
(3-Chloro-4-{5-[5-(4-methoxybenzene sulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}phenyl)carbamic Acid tert-Butyl Ester,
N-tert-Butyl-3-{5-[5-(4-iodo-benzenesulfonyl)-2,4-dioxothiazol-idin-5-yl]-pent-1-ynyl}-4-methyl-benzamide,
(3-{5-[5-(4-Iodobenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]-pent-1-ynyl}-4-methylphenyl)carbamic Acid tert-Butyl Ester,
(4-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxo-thiazolidin-5-yl]pent-1-ynyl}-3-methylphenyl)carbamic Acid tert-Butyl Ester,
(3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-4-methylphenyl)carbamic Acid tert-Butyl Ester,
(4-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-3-trifluoromethylphenyl)carbamic Acid tert-Butyl Ester,
N-tert-Butyl-3-{5-[5-(4-methoxy-benzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-4-methyl-benzamide,
5-(4-Methoxybenzenesulfonyl)-5-[5-(4-trifluoromethylphenyl)pent-4-ynyl]-thiazolidine-2,4-dione,
5-(4-Methoxybenzenesulfonyl)-5-[5-(4-trifluoromethoxyphenyl)pent-4-ynyl]-thiazolidine-2,4-dione,
3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxo-thiazolidin-5-yl]-pent-1-ynyl}-4-methylbenzoic Acid Methyl Ester,
5-[5-(4-tert-Butylphenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)-thiazolidine-2,4-dione,
5-[5-(4-tert-Butylphenyl)pent-4-ynyl]-5-(toluene-4-sulfonyl)-thiazolidine-2,4-dione,
4-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxo-thiazolidin-5-yl]pent-1-ynyl}benzonitrile,
5-[5-(4-Methanesulfonylphenyl)-pent-4-ynyl]-5-(toluene-4-sulfonyl)-thiazolidine-2,4-dione,
4-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-3-methylbenzoic Acid Methyl Ester,
5-(4-Methoxybenzenesulfonyl)-5-[5-(4-pyrrol-1-yl-phenyl)pent-4-ynyl]-thiazolidine-2,4-dione,
5-(4-Iodo-benzenesulfonyl)-5-[5-(4-pyrrol-1-yl-phenyl)pent-4-ynyl]-thiazolidine-2,4-dione,
5-[5-(4-Pyrrol-1-ylphenyl)pent-4-ynyl]-5-(4-trifluoromethoxybenzenesulfonyl) -thiazolidine-2,4-dione,
5-(3-Methoxybenzenesulfonyl)-5-(5-thiophen-2-yl-pent-4-ynyl)-thiazolidine-2,4-dione,
5-(4-Methylphenylsulfonyl)-5-(5-thiophen-2-yl-pent-4-ynyl)-thiazolidine-2,4-dione,
5-(4-Methoxybenzenesulfonyl)-5-(5-thiophen-2-yl-pent-4-ynyl)-thiazolidine-2,4-dione,
5-(4-Methoxybenzenesulfonyl)-5-(3-pyridin-3-ylprop-2-ynyl)-thiazolidine-2,4-dione,
5-(3-Thiophen-2-yl-prop-2-ynyl)-5-(toluene-4-sulfonyl)-thiazolidine-2,4-dione,
5-(3-Biphenyl-4-yl-prop-2-ynyl)-5-(toluene-4-sulfonyl)-thiazolidine-2,4-dione,
5-[3-(4-Phenoxyphenyl)prop-2-ynyl]-5-(toluene-4-sulfonyl)-thiazolidine-2,4-dione,
5-(3-Biphenyl-4-yl-prop-2-ynyl)-5-(4-methoxybenzenesulfonyl)-thiazolidine-2,4-dione,
5-(5-Pyridin-3-yl-pent-4-ynyl)-5-(toluene-4-sulfonyl)-thiazolidine-2,4-dione,
5-[5-(5-Amino-2-methylphenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)-thiazolidine-2,4-dione,
(3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-4-methylphenyl)carbamic Acid Benzyl Ester,
(3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-4-methylphenyl)carbamic Acid 4-Nitro-Benzyl Ester,
(3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-4-methylphenyl)carbamic Acid 4-Chloro-phenyl Ester,
(3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-4-methylphenyl)carbamic Acid Methyl Ester,
(3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-4-methylphenyl)carbamic Acid Isopropyl Ester,
(3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-4-methylphenyl)carbamic Acid Neopentyl Ester,
(3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-4-methylphenyl)carbamic Acid Butyl Ester,
(3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-4-methylphenyl)carbamic Acid Isobutyl,
N-[3-(5-{5-[(4-Methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl]-2-methylpropanamide,
N-[3-(5-{5-[(4-Methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl]-3,3-dimethylbutanamide,
N-[3-(5-{5-[(4-Methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl]-2,2-dimethylpropanamide,
N-[3-(5-{5-[(4-Methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl]-2-phenylacetamide,
N-Benzyl-Nxe2x80x2-[3-(5-{5-[(4-methoxyphenyl)-sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}1-pentynyl)-4-methylphenyl]urea,
N-(4-Methoxyphenyl)-Nxe2x80x2-[3-(5-{5-[(4-methoxy phenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl]urea,
N-(4-Chlorophenyl)-Nxe2x80x2-[3-(5-{5-[(4-methoxy-phenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl]urea,
N-[3-(5-{5-[(4-Methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)methylphenyl]-Nxe2x80x2-(4-methylphenyl)urea,
4-Chloro-N-[3-(5-{5-[(4-methoxyphenyl)-sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl]benzamide,
4-Methoxy-N-[3-(5-{5-[(4-methoxyphenyl)-sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl]benzamide,
N-[3-(5-{5-[(4-Methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl][1,1xe2x80x2-biphenyl]-4-carboxamide,
4-(tert-Butyl)-N-[3-(5-{5-[(4-methoxyphenyl)-sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl]benzamide,
5-[5-(4-Chlorophenyl)-4-pentynyl]-5-[(5-chloro-2-thienyl)sulfonyl]-1,3-thiazolidine-2,4-dione,
5-[5-(4-Chlorophenyl)-4-pentynyl]-5-(2-thienylsulfonyl)-1,3-thiazolidine-2,4-dione,
5-[5-(4-Chlorophenyl)-4-pentynyl]-5-[(3,4-dimethoxyphenyl)sulfonyl]-1,3-thiazolidine-2,4-dione,
5-[5-(4-Chlorophenyl)-4-pentynyl]-5-{[4-(4-pyridinyloxy)phenyl]sulfonyl}-1,3-thiazolidine-2,4-dione,
5-[5-(4-Chlorophenyl)-4-pentynyl]-5-{[5-(2-pyridinyl)-2-thienyl]sulfonyl}-1,3-thiazolidine-2,4-dione,
5-[(5-Chloro-2-thienyl)sulfonyl]-5-[5-(2,5-dichlorophenyl)-4-pentynyl]-1,3-thiazolidine-2,4-dione,
5-[5-(2,5-Dichlorophenyl)-4-pentynyl]-5-(2-thienylsulfonyl)-1,3-thiazolidine-2,4-dione,
5-[5-(2,5-Dichlorophenyl)-4-pentynyl]-5-[(3,4-dimethoxyphenyl)sulfonyl]-1,3-thiazolidine-2,4-dione,
5-[5-(2,5-Dichlorophenyl)-4-pentynyl]-5-{[4-(4-pyridinyloxy)phenyl]sulfonyl}-1,3-thiazolidine-2,4-dione,
5-[5-(2,5-Dichlorophenyl)-4-pentynyl]-5-{[5-(2-pyridinyl)-2-thienyl]sulfonyl}-1,3-thiazolidine-2,4-dione,
tert-Butyl 3-(5-{5-[(5-chloro-2-thienyl)-sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenylcarbamate,
tert-Butyl 3-{5-[2,4-dioxo-5-(2-thienylsulfonyl)-1,3-thiazolidin-5-yl]-1-pentyn-yl}-4-methylphenylcarbamate,
tert-Butyl 3-(5-{5-[(3,4-dimethoxy-phenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenylcarbamate,
tert-Butyl 3-[5-(2,4-dioxo-5-{[4-(4-pyridinyloxy)phenyl]sulfonyl}-1,3-thiazolidin-5-yl)-1-pentynyl]-4-methylphenyl-carbamate,
tert-Butyl 3-[5-(2,4-dioxo-5-{[5-(2-pyridinyl)-2-thienyl]sulfonyl}-1,3-thiazolidin-5-yl)1-pentynyl]-4-methylphenylcarbamate,
N-(tert-Butyl)-3-(5-{5-[(5-chloro-2-thienyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylbenzamide,
N-(tert-Butyl)-3-{5-[2,4-dioxo-5-(2-thienylsulfonyl)-1,3-thiazolidin-5-yl]-1-pentynyl}-4-methylbenzamide,
N-(tert-Butyl)-3-(5-{5-[(3,4-dimethoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylbenzamide,
N-(tert-Butyl)-3-[5-(2,4-dioxo-5-{[5-(2-pyridinyl)-2-thienyl]sulfonyl}-1,3-thiazolidin-5-yl)-1-pentynyl]-4-methylbenzamide,
4-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-3-methylbenzoic Acid,
N-(4-Chlorobenzyl)-3-[5-(4-methoxybenzenesulfonyl)-2,4-dioxo-thiazolidin-4-yl]propionamide,
N-[2-(4-Chlorophenyl)ethyl]-3-[5-(4-methoxybenzenesulfonyl)-2,4-dioxo-thiazolidin-5-yl]propionamide,
5-[(4Z)-5-(4-Chloro-phenyl)pent-4-enyl]-5-(toluene-4-sulfonyl)-thiazolidine-2,4-dione,
5-[(4E)-5-(4-Chlorophenyl)pent-4-enyl]-5-(4-methoxybenzenesulfonyl)thiazolidine-2,4-dione,
5-[3-(4-Chlorophenyl)propyl]-5-(4-methoxybenzenesulfonyl)-thiazolidine-2,4-dione,
5-[5-(3-Aminophenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)-thiazolidine-2,4-dione,
5-(3-Phenylalkyl)-5-(toluene-4-sulfonyl)-thiazolidine-2,4-dione,
Enantiomer of(3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-4-methylphenyl)carbamic Acid tert-Butyl Ester (less polar),
Enantiomer of (3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-4-methylphenyl)carbamic Acid tert-Butyl Ester (more polar),
5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-methoxyphenylsulfinyl)-thiazolidine-2,4-dione,
Benzyl 5-[5-(5-{[(benzyloxy)carbonyl]-amino}-2-methylphenyl)pent-4-ynyl]-5-[(4-methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidine-3-carboxylate,
4-Nitrobenzyl 5-[(4-methoxyphenyl) sulfonyl]-5-{5-[2-methyl-5-({[(4-nitro benzyl)oxy]carbonyl}amino) phenyl]pent-4-ynyl}-2,4-dioxo-1,3-thiazolidine-3-carboxylate,
Methyl 5-(5-{5-[(methoxycarbonyl)amino]-2-methylphenyl}pent-4-ynyl)-5-[(4-methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidine-3-carboxylate,
Isopropyl 5-(5-{5-[(isopropoxycarbonyl)-amino]-2-methylphenyl}pent-4-ynyl)-5-[(4-methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidine-3-carboxylate,
Neopentyl 5-[(4-methoxyphenyl)sulfonyl]-5-[5-(2-methyl-5-{[(neopentyloxy)carbonyl]-amino}phenyl)pent-4-ynyl]-2,4-dioxo-1,3-thiazolidine-3-carboxylate,
Butyl 5-(5-{5-[(butoxycarbonyl)amino]-2-methylphenyl}pent-4-ynyl)-5-[(4-methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidine-3-carboxylate,
Isobutyl 5-(5-{5-[(isobutoxycarbonyl)-amino]-2-methylphenyl}pent-4-ynyl)-5-[(4-methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidine-3-carboxylate,
5-[5-(4-Chlorophenyl)pent-4-ynyl]-3-(3-imidazol-1-yl-propyl)-5-(4-methoxybenzenesulfonyl)-thiazolidine-2,4-dione,
5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)-3-methyl-thiazolidine-2,4-dione,
5-[5-(4-Chlorophenyl)pent-4-ynyl]-3-(2,4-diethoxybenzyl)-5-(toluene-4-sulfonyl)thiazolidine-2,4-dione,
5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-iodobenzenesulfonyl)-3-(4-nitrobenzyl)thiazolidine-2,4-dione, and
5-[5-(2,5-Dichlorophenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)-2,4-dioxothiazolidine-3-carboxylic acid 2-methoxy ethyl ester.
The present invention also discloses a process for the preparation of a compound of Formula (I): 
wherein:
Ar is 1-naphthyl, 2-naphthyl, 8-quinolinyl, 2-thienyl, 5-chloro-2-thienyl, 5-(2-pyridyl)-2-thienyl, 2-pyridinyl, substituted 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 2-quinolinyl, 2-pyrimidinyl, 2-benzoxazolyl, 2-benzthiazolyl, 2-benzimidazolyl, 2-furanyl, 2-benzo-[b]-furanyl, 2-benzo-[b]-thienyl or a moiety of the formula: 
R1 is hydrogen, fluoro, bromo, chloro, iodo, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms,4-pyridyloxy, azido, nitro, acetamido, trifluoromethoxy, phenoxy, or benzyloxy;
R2 is hydrogen, fluoro, bromo, chloro, iodo, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, trifluoromethoxy, phenoxy, or benzyloxy;
m is 0, 1 or 2;
R6 is hydrogen;
Y is 2-methoxyethyl, alkyl is 1 to 6 carbon atoms, benzyl, or substituted benzyl;
W is 
xe2x80x83Exe2x80x94 and Zxe2x80x94xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CONHxe2x80x94, xe2x80x94CONHCH2xe2x80x94, xe2x80x94CONHCH2CH2xe2x80x94 or xe2x80x94CH2xe2x80x94CH2xe2x80x94;
n is an integer of 1 to 9;
Arxe2x80x2 is thienyl, pyridinyl or a moiety of the formula: 
R3, R4, R5, are independently selected from hydrogen, alkoxy of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms, fluoro, bromo, chloro, iodo, nitro, amino, hydroxy, azido, cyano, phenyl, phenoxy, trifluoromethyl, trifluoromethoxy, methanesulphonyl, 1-pyrrolyl, xe2x80x94CO2R7, xe2x80x94CONHR8, xe2x80x94CH2CONHR9, xe2x80x94NHCO2R10, xe2x80x94NHCOR11, and xe2x80x94NHCONHR12;
R7 is selected from H, and alkyl of 1 to 6 carbon atoms,
R8 is selected from H, and alkyl of 1 to 6 carbon atoms;
R9 is selected from H, and alkyl of 1 to 6 carbon atoms;
R10 is selected from alkyl of 1 to 6 carbon atoms, benzyl, nitrobenzyl, and chlorophenyl;
R1 is selected from alkyl of 1 to 6 carbon atoms, benzyl, phenyl, halophenyl, alkyl(1 to 6 carbon atoms)phenyl, alkoxy(1 to 6 carbon atoms)phenyl, and biphenyl;
R12 is benzyl, alkyl of 1 to 6 carbon atoms, alkoxy(1 to 6 carbon atoms)phenyl, halophenyl, and alkyl(1 to 6 carbon atoms)phenyl;
provided that when W is 
xe2x80x83then n is other than 2;
further provided that when n is 1, m is 0 or 2, R6 is H and W is 
xe2x80x83then:
Ar is not phenyl, 2-naphthyl, alkyl substituted phenyl, alkoxy substituted phenyl, halogen substituted phenyl, 2-pyridinyl, substituted 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 2-quinolinyl, 2-pyrimidinyl, 2-benzoxazolyl, 2-benzthiazolyl, 2-benzimidazolyl, 2-furanyl, 2-benzo-[b]-furanyl, 2-thienyl, 2-benzo-[b]-thienyl; and
Arxe2x80x2 is not phenyl, alkyl substituted phenyl, perfluoroalkyl (mono or di)substituted phenyl, halogen substituted phenyl, alkoxy substituted phenyl, perfluoroalkoxy substituted phenyl and alkylthio substituted phenyl;
or pharmaceutically acceptable salts thereof,
which comprises:
reacting a compound of the formula: 
with an alkyne of the formula:
Arxe2x80x2Wxe2x80x94(CH2)mxe2x80x94LG
wherein LG is a leaving group
in the presence of a base to give a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
It is understood that the definition of compounds of Formula (I) when R1 to R12, contain asymmetric carbons, encompass all possible stereoisomers and mixtures thereof which possess the activity discussed below. In particular, the definition encompasses racemic modifications and any optical isomers which possess the indicated activity. Optical isomers may be obtained in pure form by standard separation techniques or enantiomer specific synthesis. It is understood that this invention encompasses all crystalline forms of compounds of Formula (I). The pharmaceutically acceptable salts of the basic compounds of this invention are those derived from such organic and inorganic acids as: lactic, citric, acetic, tartaric, fumaric, succinic, maleic, malonic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, and similarly known acceptable acids. Where R1 to R12, or Y contains a carboxyl group, salts of the compounds in this invention may be formed with bases such as alkali metals (Na, K, Li) or alkaline earth metals (Ca or Mg).
For the compounds of Formula (I) defined above and referred to herein, unless otherwise noted, the following terms are defined:
Halogen, as used herein means chloro, fluoro, bromo and iodo.
Alkyl as used herein means a branched or straight chain having from 1 to 6 carbon atoms. Exemplary alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl and hexyl.
Aryl as used herein means an aromatic radical wherein Ar is 1-naphthyl, 2-naphthyl, 8-quinolinyl, 2-thienyl, 5-chloro-2-thienyl, 5-(2-pyridyl)-2-thienyl, 2-pyridinyl, substituted 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 2-quinolinyl, 2-pyrimidinyl, 2-benzoxazolyl, 2-benzthiazolyl, 2-benzimidazolyl, 2-furanyl, 2-benzo-[b]-furanyl, 2-benzo-[b]-thienyl or a moiety of the formula: 
and further defined an aromatic radical Arxe2x80x2 is thienyl, pyridinyl or a moiety of the formula: 
Alkoxy as used herein means an xe2x80x94O-alkyl group in which the alkyl group is as previously described. Exemplary alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, and t-butoxy.
Alkyne as used herein means an alkynyl group 
is present.
Phenyl as used herein refers to a 6-membered aromatic ring. Carbamic acid ester is xe2x80x94NHCO2R10 where preferred R10 is alkyl of 1 to 6 carbon atoms.
Substituted carboxamide is xe2x80x94CONHR8 wherein R8 is alkyl of 0.1 to 6 carbon atoms.
Substituted 2-pyridinyl and substituted benzyl, unless otherwise provided for herein, preferably has from 1 to 3 substituents independently selected from fluoro, chloro, bromo, iodo, nitro, cyano, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, trifluoromethyl and trifluoromethoxy.
This invention provides a method of treatment, by administration of an effective amount of compounds of Formula (I), of ras oncogene-dependent tumors, which include cancers of the pancreas, colon, bladder, and thyroid; a method of controlling metastasis, suppressing angiogenesis, and inducing apoptosis; a method of treating Ras-associated proliferative diseases other than cancer, which include restenosis, neuro-fibromatosis, endometriosis, and psoriasis The compounds of Formula (I) may also inhibit prenylation of proteins other than Ras, and thus provide a method of treatment of diseases associated with other prenyl modifications of proteins. The compounds of Formula (I) inhibit farnesyl-protein transferase and the farnesylation of the oncogene protein Ras. Thus, this invention further provides a method of inhibiting farnesyl protein transferase, (e.g., Ras farnesyl protein transferase) in mammals, especially humans, by the administration of an effective amount of the compounds of Formula (I). The administration of the compounds of this invention to patients, to inhibit farnesyl protein transferase, is useful in the treatment of the cancers and other diseases described below.
This invention provides a method for inhibiting or treating the abnormal growth of cells, including transformed cells by administering an effective amount of a compound of Formula (I). Abnormal growth of cells refers to cell growth independent of normal regulatory mechanisms (e.g., loss of contact inhibition). This includes abnormal growth of tumor cells (tumors) expressing an activated Ras oncogene; tumor cells in which the Ras protein is activated as a result of oncogenic mutation in another gene; and benign and malignant cells of other proliferative diseases in which aberrant Ras activation occurs.
This invention also provides a method for inhibiting or treating tumor growth by administering an effective amount of a compound of Formula (I), described herein, to a mammal (e.g., a human) in need of such treatment. In particular, this invention provides a method for inhibiting or treating the growth of tumors expressing an activated Ras oncogene by administration of an effective amount of a compound of Formula (I). Examples of tumors which may be inhibited or treated include, but are not limited to, lung cancer (e.g., lung adenocarcinoma), pancreatic cancers (e.g., pancreatic carcinoma such as, for example, exocrine pancreatic carcinoma), colon cancers (e.g., colorectal carcinomas, such as, for example, colon adenocarcinoma and colon adenoma), myeloid leukemias (for example, acute myelogenous leukemia (AML)), thyroid follicular cancer, myelodysplastic syndrome (MDS), bladder carcinoma, epidermal carcinoma, breast cancer and prostate cancer.
This invention also provides a method for inhibiting or treating proliferative diseases, both benign and malignant, wherein Ras proteins are aberrantly activated as a result of oncogenic mutation in other genes-i.e., the Ras gene itself is not activated by mutation to an oncogenic form-with said inhibition or treatment being accomplished by the administration of an effective amount of a compound of Formula (I), to a mammal (e.g., a human) in need of such treatment. For example, the benign proliferative disorder neurofibromatosis, or tumors in which Ras is activated due to mutation or overexpression of tyrosine kinase oncogenes (e.g., neu, src, abl, Ick, and fyn), may be inhibited or treated by the compounds of Formula (I). Additionally, this invention provides a method of inhibition or treating the abnormal growth of cells, by administration of an effective amount of compounds of Formula (I), of ras-oncogene-dependent tumors, which tumors include cancers of the pancreas, colon, bladder, and thyroid. Without wishing to be bound by theory, these compounds may function through the inhibition of G-protein function, such as ras p21, by blocking G-protein isoprenylation, thus making them useful in the treatment of proliferative diseases such as tumor growth and cancer. Without wishing to be bound by theory, compounds of Formula (I) inhibit Ras farnesyl-protein transferase, and thus antiproliferative activity of ras-transformed cells and other prenyl modifications of proteins.
Compounds of this invention may be prepared according to the methods and procedures described in U.S. Pat. Nos. 5,605,918 and 5,574,051, which are hereby incorporated herein by reference; in Wrobel, J., et al., J. Med. Chem. 1998, 41 (7), 1084-91 and as outlined in Schemes I through XI described herein. 
As shown in Scheme I, arylthiol VI where Ar is hereinbefore defined is reacted with 2 or more equivalents of a strong base such as lithium diisopropylamide, lithium bis(trimethylsilylamide), and the like followed by reaction with one or more equivalents of 5-bromothiazolidine-2,4-dione IV(Zask et al, J. Med. Chem. 1990, 33, 1418-1423) to produce a 5-arylsulfanylthiazolidine-2,4-dione VII in an aprotic solvent such as tetrahydrofuran (THF) or hexane at temperatures (e.g. 0xc2x0 to xe2x88x9278xc2x0 C.) followed by warming to about ambient temperature for 1 to 10 h.
The 5-arylsulfanylthiazolidine-2,4-dione VII may then be oxidized to afford 5-arylsulfonylthiazolidine-2,4-dione V. Following the procedure of Zask et al (J. Med. Chem. 1990, 33, 1418-1423), the oxidation is conveniently performed using excess (2 to 20 equivalents) aqueous hydrogen peroxide in acetic acid at ambient or higher (30xc2x0 to 80xc2x0 C.) reaction temperatures for 1 to 10 h.
The 5-arylsulfanylthiazolidine-2,4-dione VII may also be oxidized to afford 5-arylsulfinylthiazolidine-2,4-dione Va by bubbling oxygen in the presence of isobutyraldehyde in a solvent which includes acetonitrile for 18 hours.
The 5-arylsulfonylthiazolidine-2,4-dione V may also be prepared by reacting one or more equivalents of an alkali metal arylsulfinate VIII, where M is an alkali metal with 5-bromothiazolidine-2,4-dione IV in suitable solvents which include polar aprotic solvents such as N,N-dimethylformamide (DMF), tetrahydrofuran (THF) or protic solvents such as low molecular weight alcohols (methyl alcohol, ethyl alcohol and isopropanol and the like), or water.
Alternatively, the alkali metal arylsulfinate VIII can also be prepared by reduction of an arylsulfonyl chloride with sodium iodide in acetone (Harwood, Julia, and Thuillier, Tetrahedron, 1980,36, 2483-2487). 
As shown in Scheme II arylalkynes XI, wherein Arxe2x80x2 is as previously defined, and LG is a suitable leaving group which include iodo, bromo and p-toluenesulfonyloxy, can be prepared via a two step process from commercially available aryl iodides or aryl bromides where Arxe2x80x2 is hereinbefore defined or those aryl iodides or aryl bromides described in the the art. In the first step, alcohol X is prepared by the reaction of the appropriate aryl iodide or bromide with one or more equivalents of a terminal alkyne-ol IX, in the presence of a catalytic amount of a palladium(II) reagent such as dichlorobis(triphenylphosphine)palladium(II) and a catalytic amount of a copper(I) reagent such as copper(I) iodide. This reaction is also performed in the presence of one or more equivalents of a secondary or tertiary amine such as diethylamine or triethylamine. The secondary or tertiary amine may be used as solvent, or alternatively a halocarbon solvent such as chloroform may be employed. Temperatures up to 80xc2x0 C. are commonly used, with reaction times varying from 1 h to 2 days. Alkyne XI wherein Arxe2x80x2 is hereinbefore defined and LG is p-toluenesulfonyloxy is most conveniently prepared from alcohol X by reaction with p-toluenesulfonyl chloride in a solvent such as dichloromethane and in the presence of N,N-dimethylaminopyridine and triethylamine at 0xc2x0 C. to 30xc2x0 C., from one hour to 6 hours; or when LG is iodo, alcohol X is reacted with iodine, in the presence of triphenylphosphine and imidazole in a solvent such as ether, or acetonitrile, at a temperature of 0xc2x0 C. to room temperature for 8 hours to 24 hours; alternatively alkyne XI wherein LG is p-toluenesulfonyloxy is reacted with sodium iodide in acetone at room temperature from 8 hours to 36 hours to give alkyne XI wherein LG is iodo; or when LG is bromo, X is reacted with carbon tetrabromide in the presence of triphenylphosphine in a solvent such as THF at 0xc2x0 C. to 35xc2x0 C. for 8 hours to 72 hours to give alkyne XI wherein LG is bromo. 
Referring to Scheme III: 5-substituted-5-(arylsulfanyl)thiazolidine-2,4-diones of Formula (I) may be prepared by reaction of the appropriate 5-(arylsulfanyl)thiazolidine-2,4-dione VII with 2 or more equivalents of a base. Two equivalents of base effect deprotonation of both the thiazolidinedione nitrogen atom and at the C-5 position to form a dianion. Common bases to accomplish this deprotonation include alkali metal hydrides such as sodium hydride, alkali metal alkyls such as butyl lithium or alkali metal amide bases such as lithium diisopropylamide or lithium bis(trimethylsilyl)amide. Convenient solvents include THF and DMF. Reaction temperatures may be varied from xe2x88x9278xc2x0 C. to room temperature. Two minutes to 1 h after the base is introduced, one or more equivalents of the appropriate alkylating agent, alkyne XI is added to the reaction mixture and this is allowed to stir at 0xc2x0 C. or room temperature for a period of from 1 h to 3 days. Alkylation occurs primarily on the thiazolidindione C-5 carbon atom to afford the 5-substituted-5-(arylsulfanyl)thiazolidine-2,4-dione of Formula (I), m=0 which may then be oxidized to afford 5-arylsulfonylthiazolidine-2,4-dione of Formula (I) wherein m=2 by the procedure of Zask et al (J. Med. Chem. 1990, 33, 1418-1423). The oxidation is conveniently performed using excess (2 to 20 equivalents) aqueous hydrogen peroxide in acetic acid at ambient or higher (30xc2x0 C. to 80xc2x0 C.) reaction temperatures for 1 to 10 h. 
Referring to Scheme IIIa: 5-substituted-5-(arylsulfinyl)thiazolidine-2,4-diones of Formula (I) may be prepared by reaction of the appropriate 5-(arylsulfinyl)thiazolidine-2,4-dione Va in the presence of a base. Common bases include alkali metal hydrides such as sodium hydride, alkali metal alkyls such as butyl lithium or alkali metal amide bases such as lithium diisopropylamide or lithium bis(trimethylsilyl)amide. Convenient solvents include THF and DMF. Reaction temperatures may be varied from xe2x88x9278xc2x0 C. to room temperature. Two minutes to 1 h after the base is introduced, one or more equivalents of the appropriate alkylating agent, alkyne XI is added to the reaction mixture and this is allowed to stir at 0xc2x0 C. or room temperature for a period of from 1 h to 3 days. Alkylation occurs primarily on the thiazolidindione C-5 carbon atom to afford the 5-substituted-5-(arylsulfinyl)thiazolidine-2,4-dione of Formula (I), m =1. 
As shown in Scheme IV: 5-substituted-5-(arylsulfonyl)thiazolidine-2,4-diones of Formula (I) may be prepared by reaction of the appropriate 5-(arylsulfonyl)thiazolidine-2,4-dione V with 2 or more equivalents of a base. Two equivalents of base effect deprotonation of both the thiazolidinedione nitrogen atom and at the C-5 position to form a dianion. Common bases to accomplish this deprotonation include alkali metal hydrides such as sodium hydride, alkali metal alkyls such as butyl lithium or alkali metal amide bases such as lithium diisopropylamide or lithium bis(trimethylsilyl)amide. Convenient solvents include THF and DMF. Reaction temperatures vary from xe2x88x9278xc2x0 C. to room temperature. Two minutes to 1 h after the base is introduced, one or more equivalents of the appropriate alkylating agent, alkyne XI is added to the reaction mixture and the reaction is allowed to stir at 0xc2x0 C. or room temperature for a period of from 1 h to 3 days. Alkylation occurs exclusively on the thiazolidindione C-5 carbon atom to afford the 5-substituted-5-(arylsulfonyl)thiazolidine-2,4-dione of formula (I).
As shown in Scheme V, a compound of Formula (I), wherein at least one of R3, R4, or R5 of the moiety: 
is a nitro group, and as shown in formula Ixe2x80x2 where R3 is a nitro group, is reacted with a reducing agent, such as iron in acetic acid or tin in hydrochloric acid, or other agents known to effect this reduction to give an amine XIII. 
As further shown in Scheme V, compounds of Formula (I), wherein at least one of R3, R4, or R5 is amino, as shown in amine XIII can be prepared by hydrolysis of carbamate XII, wherein at least one of R3, R4, or R5 of Formula (I) is a t-butoxycarbonylamino group, by the use of an acid, such as trifluoroacetic acid, or aqueous hydrochloric acid at 0xc2x0 C. to 60xc2x0 C., from 0.5 h to 4 h.
Substituted amine XIV, wherein at least one of R3, R4, or R5 is xe2x80x94NHCO2R10 wherein R10 is selected from alkyl of 1 to 6 carbon atoms, benzyl, nitrobenzyl, chlorophenyl; substituted amine XV, wherein at least one of R3, R4, or R5 is xe2x80x94NHCOR11, wherein R11 is selected from alkyl of 1 to 6 carbon atoms, benzyl, phenyl, alkyl(1 to 6 carbon atoms)phenyl, alkoxy(1 to 6 carbon atoms)phenyl, biphenyl; substituted amine XVI wherein at least one of R3, R4, or R5 is xe2x80x94NHCONHR12 wherein R12 is benzyl, alkoxy(1 to 6 carbon atoms)phenyl, halophenyl, alkyl(1 to 6 carbon atoms)phenyl can each be prepared by reaction of the amine XIII, respectively with an appropriate alkoxycarbonyl or aryloxycarbonylchloride; acid chloride, or similarly activated acyl compound; or an isocyanate, in an inert solvent, in the presence of an acid scavenger such as triethylamine, at 0xc2x0 C. to 40xc2x0 C., for 0.5 h to 24 h. 
Referring to Scheme VI: compounds of formula (I), wherein at least one of R3, R4, or R5 is the azido group, as in azide XVII may be prepared from amine XIII, by reaction with sodium nitrite in acetic acid at 0xc2x0 C. to 20xc2x0 C., for 10 min to 30 min, followed by a metal azide, such as lithium azide for 1 h to 3 h at 10xc2x0 C. to 25xc2x0 C. 
Referring to Scheme VII: compounds of formula (I), wherein at least one of R3, R4, or R5 is a carboxyl group as in carboxylic acid XIX can be prepared from the corresponding ester, such as the methyl ester as in ester XVIII by hydrolysis with a base such as potassium carbonate in a solvent such as methanol, or water, followed by acidification with an acid, such as hydrochloric acid. 
Referring to Scheme VIII: Compounds of Formula (I), wherein Arxe2x80x2 is hereinbefore define and at least one of R3, R4, or R5 are as described above, and W is Zxe2x80x94xe2x80x94CHxe2x95x90CHxe2x80x94 in alkene XXI may be prepared from the corresponding compounds of formula (I) wherein W is 
in alkyne XX by reduction with hydrogen and a catalyst, such as platinum or palladium in a solvent such as an alcohol, or THF at 0xc2x0 to 30xc2x0 C. for xc2xd to 8 h; 
As shown in Scheme IX: compounds of Formula (I) as in alkene XXVI, wherein either R3, R4, and R5 are as previously defined as substituents on Arxe2x80x2, and W is Exe2x80x94xe2x80x94CHxe2x95x90CHxe2x80x94, may be prepared by alkylation of 5-arylsulfonylthiazolidine-2,4-dione V with an alkene XXV under conditions as described in Scheme III for the corresponding alkyne. Alkenes XXIV wherein W is Exe2x80x94xe2x80x94CHxe2x95x90CHxe2x80x94, can be prepared by coupling an iodophenyl compound where Arxe2x80x2 is hereinbefore defined with an E-stannane XXII in the presence of tetrakistriphenyl-phosphine palladium(0) and copper(I) iodide in a solvent such as DMF at room temperature for 1 h to 3 days and subsequent conversion to alcohol XXIII to alkene XXIV, wherein LG is iodo, may be accomplished in a manner analogous to that shown in Scheme II. A compound such as XXV, above, wherein LG is a leaving group, such as, bromo or iodo is used to alkylate 5-arylsulfonylthiazolidine-2,4-dione V as described herein before in Scheme III. 
Referring to Scheme X: compounds of formula (I), wherein Arxe2x80x2 is herein before described and W is xe2x80x94CH2xe2x80x94CH2xe2x80x94 as in dione XXVII, can be prepared from a compound of formula (I) wherein W is either 
or Exe2x80x94 or Zxe2x80x94xe2x80x94CHxe2x95x90CHxe2x80x94, by hydrogenation in the presence of palladium or platinum in a solvent such as methanol plus 5% water; alternatively, 5-arylsulfonylthiazolidine-2,4-dione V can be alkylated with XXVIII to give dione XXVII.
The ability of the compounds of this invention to inhibit FPTase was evaluated in the standard pharmacological in vitro test procedures described below. Data for representative examples is summarized in Table I.
Enzyme test procedure: FPTase inhibition in vitro assay was performed according to James, G. L., Brown, M. S., and Goldstein, J. L., Methods in Enzymology, 1995, 255, 38-46; and Garcia, M. A., et al., J. Biol. Chem., 1993, 268, 18415-18420.
Materialsxe2x80x94Purified FPTase (Moomaw, J. F. and Casey, P. J., J. Biol. Chem., 1992, 267, 17438-17443), purified His6-Ras, inhibitor compounds at 10 mg/ml or 10 mM in 100% DMSO, 3H-FPP (50,000 dpm/pmol) Amersham, TCA/SDS (6%/2%), TCA (6%), Glass fiber filters (0.22-0.45 m), vacuum manifold or 96 well filtration plates.
Methodsxe2x80x941. Dilute FPTase inhibitors from stock solutions to 2.5xc3x97 in 2.5% DMSO, 10 mM DTT, 0.5% octyl-B-glucoside. 2. Solution #1 is added to FPTase reaction in a volume of 20 ml. 3. Standard reaction mix, 50 ml, contains 50 mM Tris (7.5), 10 mM ZnCl2, 3 mM MgCl2, 20 mM KCl, 5 mM DTT, 0.2% octyl-B-glucoside, 1% DMSO, 40 mM His6-Ras, 10 ng FPTase, and various concentrations of FPTase inhibitors. 4. Incubate for 30-90 min at 250xc2x0 C. 5. Stop reactions with TCA/SDS (6%/2%), hold at 4xc2x0 C. for 45-60 min. 6. Filter by manifold or 96 well plate, wash filter 3-5xc3x97 with TCA (6%). 7. Add scintillant to filters, measure 3H-FPP incorporation into Ras protein.
Analysis of Resultsxe2x80x94Percent inhibition by test compounds is determined by the following:
(cpm from precipitated Ras with test compounds)xe2x88x92(background cpm)xc3x97100=% inhibition.
(cpm from precipitated Ras without test compounds)xe2x88x92(background cpm)
Cell-based test procedure: Tumor inhibition in vitro assay was performed according to P. Skehan, R. Storeng, D. Scudiero, A. Monks, J. McMohan, D. Vistica, J. Warren, H. Bokesh, S. Kenney, and M. R. Boyd, J. Natl. Cancer Instit., 1990, 82 (13), 1107-1112; L. V. Rubinstein, R. H. Shoemaker, K. D. Paull, R. M. Simon, S. Tosini, P. Skehan, D. A. Scudiero, A. Monks, and M. R. Boyd, J. Natl. Cancer Instit., 1990, 82 (13), 1113-1118; A. Monks, et al., J. Natl. Cancer Instit., 1991, 83, 757-766; M. R. Boyd and K. D. Paull, Drug Development Res., 1995, 34, 91-109; and S. P. Fricker and R. G. Buckley, Anticancer Research, 1996, 16, 3755-3760.
Materialsxe2x80x94Cell Lines: Human tumor cell lines LS174T, HTB39, LoVo and CaCo2. Cell Media: RPMI 1640 (or DMEM medium and McCoy""s medium) with 10% Fetal Bovine Serum supplemented with L-glutamine and Pennicilin/Streptomycin. Compounds: Supplied usually as a 10 mM stock in 100% DMSO. Normal Saline: 150 mM NaCl Trichloroacetic Acid (TCA): 50% (w/v) in water. Sulforhodamine (SRB): 0.4% (w/v) in 1% Acetic Acid. Tris Base: 10 mM in water.
Methodsxe2x80x94Cells are plated at 2000 cells per well, per 200 xcexcl media, and allowed to adhere overnight at 37xc2x0 C. At 24 h post plating, compounds are added directly at a volume of 0.5 xcexcl. Compound is first diluted in DMSO to generate concentrations of compound or reference standard of: 1, 5, 10 and 25 xcexcM. Dilutions can be made in an identical 96 well plate so that compounds can be added using a multichannel micropipettor set at 0.5 xcexcl. The cells are then incubated for four days after which the media is removed using a 12 well manifold by first tipping the plate forward at a 45 degree angle and then inserting the manifold in an upright orientation to prevent the tips of the manifold from disturbing cells at the bottom of the plate. 200 xcexcl of normal saline is then added to each well using an 8 well multichannel pipettor, followed by the careful addition of 50 xcexcl of 50% TCA. The plates are then incubated for 2 h at 4xc2x0 C., after which the supernatant is removed using the same technique as above and the plates washed twice with 200 xcexcl water. The plates are then air dried and 50 xcexcl of SRB stock solution is carefully added so that the entire bottom of each well is covered. This again can be used using an 8 well multichannel pipettor. The SRB is incubated with fixed cells for 15 min at room temperature, after which the SRB is removed with the manifold as described above and the plates washed twice with 350 xcexcl of 1% acetic acid per well each time. The plates are then air dried after which the bound SRB is released from protein by the addition of 200 xcexcl of Tris base. Resolubilizing the SRB is aided by placing the plates on a rotator for 15-30 min. The absorbance of each well is determined at 550 or 562 nm using a microtiter plate reader.
Analysis of Resultsxe2x80x94Each compound or dilution thereof is performed in triplicate. Outliers are identified by visual inspection of the data. Each plate should have a control (vehicle only). A standard curve is constructed by plotting the concentration of compound against the average absorbance calculated at that concentration. A curve is plotted and the concentration at which the curve passes through the 50% absorbance mark seen in the control well is the IC50 calculated for that compound.
Compounds of this invention were tested in cell-based assays against human tumor cell lines DLD-1 and LoVo and ras-transformed rat fibroblast cell lines, RAT-H-ras and RAT-K-ras, and the parent cell line RAT-2, as described under Assays. The range observed for inhibition of cell growth was IC50=7 to 18 xcexcM. The results are displayed in Table I.
Compounds of this invention were tested for in vivo effects in rats against various tumors. For the compound of Example 114, when tested against a K-ras dependent human colon carcinoma (LoVo), the following results were obtained (Table II):
Examples 100, and 103, when tested in rats against Rat-2 fibroblasts transformed by oncogenic H-ras for 11 days, i.p., the following results were obtained for day 11 (Table IV):
In a similar model when tested in rats against Rat-2 fibroblasts transformed by oncogenic K-ras for 25 days, i.p, the compound of Example 100 showed no efficacy at 100 mg/kg.
Based on the results of these standard pharmacological test procedures, the compounds of this invention are useful as agents for treating, inhibiting or controlling ras-associated diseases by inhibiting farnesyl-protein transferase enzyme, when administered in amounts ranging from about 10 to about 200 mg/kg of body weight per day. A preferred regimen for optimum results would be from about 10 mg to about 100 mg/kg of body weight per day and such dosage units are employed that a total of from about 100 mg to about 1000 mg of the active compound for a subject of about 70 kg of body weight are administered in a 24 hour period.
The dosage regimen for treating mammals may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation. A decidedly practical advantage is that these active compounds may be administered in any convenient manner such as by the oral, intravenous, intramuscular or subcutaneous routes.
The active compounds may be orally administered, for example, with an inert diluent or with an assimilable edible carrier, or they may be enclosed in hard or soft shell gelatin capsules, or they may be compressed into tablets or they may be incorporated directly with the food of the diet. For oral therapeutic administration, these active compounds may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers and the like. Such compositions and preparations should contain at least 0.1% of active compound. The percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2% to about 60% of the weight of the unit. The amount of active compound in such therapeutically useful compositions is such that a suitable dosage will be obtained. Preferred compositions or preparations according to the present invention are prepared so that an oral dosage unit form contains between 10 and 1000 mg of active compound. The tablets, troches, pills, capsules and the like may also contain the following: a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose, or saccharin may be added or a flavoring agnet such as peppermint, oil of wintergreen or cherry flavoring. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets, pills or capsules may be coated with shellac, sugar or both. A syrup or elixir may contain the active compound, sucrose, as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor. Of course, any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts used. In addition, these active compounds may be incorporated into sustained-release preparations and formulations.
These active compounds may also be administered parenterally or intraperitoneally. Solutions or suspensions of these active compounds as a free base or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures therof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth or microorganisms.
The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and starage and must be prepared against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid poly-ethylene glycol), suitable mixtures thereof, and vegetable oils.
The present invention accordingly provides a pharmaceutical composition which comprises a compound of Formula (I) of this invention in combination or association with a pharmaceutically acceptable carrier. In particular, the present invention provides a pharmaceutical composition which comprises an effective amount of a compound of this invention and a pharmaceutically acceptable carrier.
As used in accordance with this invention, the term providing an effective amount of a compound means either directly administering such compound, or administering a prodrug, derivative, or analog which will form an effective amount of the compound within the body.
The present invention provides a method of treatment of ras oncogene-dependent tumors, such as cancers of the pancreas, colon, bladder, and thyroid; a method of controlling metastasis, suppressing angiogenesis, and inducing apoptosis; a method of treating Ras-associated proliferative diseases other than cancer, such as restenosis, neuro-fibromatosis, endometriosis, and psoriasis. The compounds of the present invention may also inhibit prenylation of proteins other than Ras, and thus provide a method of treatment of diseases associated with other prenyl modifications of proteins.
The invention will be more fully described in conjunction with the following specific examples which are not to be construed as limiting the scope of the invention.